Upon T-Cell Receptor (TCR) ligation, Th0 cells differentiate into distinct subsets characterized by their functions and cytokine production profiles (Mosmann and Coffinan, 1989). Th1 lymphocytes, characterized by the production of IL-2, IFN-γ and TNF-β, contribute to cellular immunity whereas Th2 lymphocytes, producing IL-4, IL-5 and IL-10, are mainly involved in humoral immunity. The generation of cell-mediated immunity against many infectious pathogens relies on the induction of the innate immune system, which in turn generates appropriate signals for adaptive immune responses (Fearon and Locksley, 1996). Bacterial lipoproteins are, among others, molecules that stimulate cells of the innate immune system to produce cytokines such as TNF-α (Radolf et al., 1991; Vidal et al., 1998) and IL-12 (Brightbill et al., 1999). Hereby, bacterial lipoproteins activate innate immune cells via Toll-like receptors (Brightbill et al., 1999; Aliprantis et al., 1999) and their signaling activity resides in the NH2-terminal triacylated lipopeptide region (Erdile et al., 1993; Weis et al., 1994). The potent capacity of bacterial lipoproteins and/or lipopeptides to induce the production of IL-12 (Brightbill et al., 1999), a key signal of the innate immune system, may in turn trigger the development of adaptive immune responses.
Numerous examples ofthe consequences on disease outcome of skewed Th1 to Th2 ratios have been reported. Polarized Th2 responses have been implicated in pathological situations, such as Leishmania major infection (Heinzel et al., 1991; Nabors et al., 1995), tuberculosis (TBC) (de Jong et al., 1997), human leprosy (Yamamura et al., 1991) and mycotic infections (Murphy et al., 1994). The contribution of Th1 cells relative to Th2 cells to the developing autoimmune response determines for a larger part whether or not this response leads to clinical disease (Racke et al., 1994; Racke et al., 1995; Leonard et al., 1995). In allergic asthma, a predominant Th2-type response has been noted (Vogel, 1997). Also the chronic autoimmune graft-versus-host disease, which develops after the administration of mismatched lymphoid cells, can be prevented by switching a Th2 response to a Th1 response through administration of IFN-γ at the time of cellular transfer (Donckier et aL, 1994).
Several methods have been proposed to modulate the Th1/Th2 response. WO9726883 describes the use of ribavirin3 to treat imbalances in lymphokine expression. WO9848805 discloses chemical compounds that suppress the Th2-type response and can be used for treating or preventing a disease caused by abnormal activation of a Th2-type immune response, such as asthma, allergic dermatitis, allergic rhinitis or systemic lupus erythematosus. However, those chemical compounds may have unwanted side effects. WO9921968 describes the use of macrophages in the function of antigen-presenting cells to redirect the balance of Th1/Th2 cell subsets during an immune response. Although the latter method is more specific, it is complicated because personalized immortalized macrophage clones should be made for each patient to be treated.
It has been demonstrated that bacterial lipoproteins may also be useful in modulating the Th1/Th2 immune response. The synthetic lipid moiety analogue of bacterial lipoproteins (i.e., the tripalmitoyl-s-glyceryl-cysteine or Pam3Cys) was reported to increase the immunogenicity of heterologous antigens (Bessler et al., 1985; Lex et al., 1986; Deres et al., 1989; BenMohamed et al., 1997). Lipopeptides derived from the outer surface lipoproteins of Borrelia burgdorferi were reported to induce Th1 phenotype development (Infante-Duarte and Kamradt, 1997). It has been reported that fusion proteins between the major OprI lipoprotein of Pseudomonas aeruginosa and heterologous peptides or proteins were found to be highly immunogenic as evidenced by the induction of strong humoral and cytotoxic T-cell responses without the need for adjuvants (PCT International Patent Publication WO9303762; Cornelis et al., 1996; Leitao et aL, 1998). There is no indication that OprI can modulate the immune response. Moreover, Ino et al. (1999) describes that OprI can act as a strong inducer of cytokines in mouse bone marrow cells. When purified OprI was added to mouse bone marrow cells, an induction of TNFα, IL-1a, IL-1b, IL-6 and granulocyte-macrophage colony stimulating was seen. However, IL-2, IFN-γ and TNF-β, typically seen in a Th1 response, were not detected. (Id.)